Erythroid differentiation of adult hematopoietic progenitor cells requires stimulation by erythropoietin (Epo), a hypoxia inducible cytokine that promotes erythroid progenitor cell survival, proliferation, differentiation and Hb production. Epo binds to its cell surface receptor and induces transcription factors that regulate erythroid gene expression such as the general erythroid factor GATA-1, the basic helix-loop-helix transcription factor, Tal1, and EKLF which is relatively specific for beta-globin expression. Epo stimulation also increases expression of its own receptor resulting in creased Epo sensitivity and response. Gamma-globin is preferentially expressed during early erythropoiesis while beta-globin expression increases with induction of EKLF. Induction of Epo receptor expression is directly linked to the increase in erythroid transcription factor expression and is mediated through corresponding binding motifs in the EPO receptor proximal promoter and downstream region flanking the transcription start site. Over expression of EPO receptor further increases erythroid transcription factor expression, globin gene transcription and erythroid differentiation. Therefore, manipulation of Epo response by direct manipulation of Epo receptor expression or Epo signaling may alter the relative expression of gamma-globin and beta-globin and the overall production of fetal hemoglobin.